Reversal of Cardiac Dysfunction After Long-Term Expression of SERCA2a by Gene Transfer in a Pre-Clinical Model of Heart Failure

Yoshiaki Kawase, Hung Q. Ly, Fabrice Prunier, Djamel Lebeche, Yanfen Shi, Hongwei Jin, Lahouaria Hadri, Ryuichi Yoneyama, Kozo Hoshino, Yoshiaki Takewa, Susumu Sakata, Richard Peluso, Krisztina Zsebo, Judith K. Gwathmey, Jean Claude Tardif, Jean François Tanguay, Roger J. Hajjar

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286 Scopus citations

Abstract

Objectives: The aim of this study was to examine the effects of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) gene transfer in a swine heart failure (HF) model. Background: Reduced expression and activity of SERCA2a have been documented in HF. Prior studies have reported the beneficial effects of short-term SERCA2a overexpression in rodent models. However, the effects of long-term expression of SERCA2a in pre-clinical large animal models are not known. Methods: Yorkshire-Landrace pigs were used (n = 16) to create volume overload by percutaneously severing chordae tendinae of the mitral apparatus with a bioptome to induce mitral regurgitation. At 2 months, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 1 (rAAV1) carrying SERCA2a under a cytomegalovirus promoter (rAAV1.SERCA2a) (n = 10; group 1) or saline (n = 6; group 2). Results: At 2 months, study animals were found to be in a compensated state of volume-overload HF (increased left ventricular internal diastolic and systolic diameters [LVIDd and LVIDs]). At 4 months, gene transfer resulted in: 1) positive left ventricular (LV) inotropic effects (adjusted peak left ventricular pressure rate of rise (dP/dt)max/P, 21.2 ± 3.2 s-1 group 1 vs. 15.5 ± 3.0 s-1 group 2; p < 0.01); 2) improvement in LV remodeling (% change in LVIDs -3.0 ± 10% vs. +15 ± 11%, respectively; p < 0.01). At follow-up, brain natriuretic peptide levels remained stable in group 1 after gene transfer, in contrast to rising levels in group 2. Further, cardiac SERCA2a expression was significantly decreased in group 2 whereas in group 1 it was restored to normal levels. There was no histopathological evidence of acute myocardial inflammation or necrosis. Conclusions: Using a large-animal, volume-overload model of HF, we report that long-term overexpression of SERCA2a by in vivo rAAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction, and improved ventricular remodeling.

Original languageEnglish
Pages (from-to)1112-1119
Number of pages8
JournalJournal of the American College of Cardiology
Volume51
Issue number11
DOIs
StatePublished - 18 Mar 2008

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